Oleanolic acid reverses Alzheimer's cognitive decline by regulating KLF5-mediated FGF13 mRNA degradation

Alzheimer's disease (AD) is the leading cause of dementia, characterized by progressive synaptic dysfunction, neuronal loss, and cognitive impairment. Current pharmacological therapies offer only symptomatic relief and fail to halt or reverse disease progression. A critical gap exists in understanding mechanisms that promote neuronal regeneration and repair. Oleanolic acid (OA), a triterpenoid, has shown neuroprotective properties, but its role in neuronal regeneration via m6A RNA methylation in AD remained unexplored, presenting a novel therapeutic avenue.

Researchers utilized a streptozotocin (STZ)-induced AD rat model to investigate oleanolic acid's effects. Rats were administered Oleanolic acid (specific dose not provided) and subjected to behavioral tests to assess cognitive functions. Neuronal stem cell (NSC) proliferation was evaluated using BrdU incorporation assays and immunofluorescence. Protein expression and RNA stability were analyzed via Western blotting, chromatin immunoprecipitation (ChIP), RNA immunoprecipitation (RIP), and MeRIP-qPCR assays. Bioinformatic predictions were employed to elucidate interactions between KLF5, YTHDF2, and FGF13 in this context.

Oleanolic acid (OA) significantly reversed cognitive impairment in the AD rat model, demonstrating improved behavioral outcomes. OA also enhanced NSC differentiation, suggesting a direct impact on neurogenesis. The study revealed a novel mechanism: OA modulated KLF5 expression, leading to the repression of YTHDF2. This repression was pivotal in the m6A-dependent RNA decay of FGF13, which in turn promoted axonal regeneration. Furthermore, FGF13 was found to harbor multiple m6A modification sites, which directly influence its mRNA stability and translation, thereby impacting neuronal polarization and migration.

The neuroprotective mechanism of OA involved the upregulation of NSCs, directly counteracting impaired neurogenesis and reduced NSC function associated with AD pathology. This highlights m6A RNA methylation as a critical regulator of neuronal regeneration.